CN114761389A - 磷脂-flavagline缀合物和将其用于靶向癌症治疗的方法 - Google Patents
磷脂-flavagline缀合物和将其用于靶向癌症治疗的方法 Download PDFInfo
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- C07F9/00—Compounds containing elements of Groups 5 or 15 of the Periodic System
- C07F9/02—Phosphorus compounds
- C07F9/547—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom
- C07F9/655—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom having oxygen atoms, with or without sulfur, selenium, or tellurium atoms, as the only ring hetero atoms
- C07F9/65515—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom having oxygen atoms, with or without sulfur, selenium, or tellurium atoms, as the only ring hetero atoms the oxygen atom being part of a five-membered ring
- C07F9/65517—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom having oxygen atoms, with or without sulfur, selenium, or tellurium atoms, as the only ring hetero atoms the oxygen atom being part of a five-membered ring condensed with carbocyclic rings or carbocyclic ring systems
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Abstract
本文公开的是磷脂醚(PLE)分子。还提供了磷脂‑flavagline缀合物。磷脂‑flavagline缀合物可包括通过连接子缀合至一种flavagline的PLE。本文还提供了治疗受试者癌症的方法和将药物靶向至受试者肿瘤或癌细胞的方法。
Description
相关申请的交叉引用
本申请请求2019年10月10日提交的美国临时专利申请No.62/913,571的权益和优先权,其内容通过引用的方式全部纳入本文。
技术领域
本公开涉及磷脂-flavagline缀合物和靶向癌症疗法。
背景技术
临床使用的大多数抗癌药的应用受限于其对所有增殖细胞的毒性,和/或无法在全部肿瘤细胞上发挥作用。具有独特药理作用的新型药剂不断地开发出来,提供了增强的靶向性,然而,这些化合物中的许多化合物依然缺少绝对肿瘤选择性,并继续因脱靶效应限制了它们的治疗应用。已经设计出抗体药物缀合物(ADCs)以结合肿瘤细胞表面特定的表位并提供了另一种靶向肿瘤细胞的方法,致力于降低相关毒性。尽管具有高选择性,只有很少的抗体药物缀合物可用于治疗,因为他们只能达到中等的细胞摄取以及有限的细胞杀灭活性。需要更有效的肿瘤靶向平台。
发明内容
在一个方面,本公开提供一种式(I)化合物或其药学可接受的盐,
其中Z是flavagline类似物。
本公开的另一方面提供一种包含本文记载化合物或其药学可接受的盐和药学可接受的载体的药物组合物。
本公开的另一个方面提供一种治疗受试者癌症的方法,所述的方法包含向受试者给予本文记载的化合物或其药学可接受的盐。
本公开的另一个方面提供了一种将药物靶向受试者肿瘤或癌症细胞的方法,所述方法包含向受试者给予本文记载的化合物或其药学可接受的盐。
在一些实施方案中,本文记载的化合物定位于或途径肿瘤或癌细胞的细胞质或细胞器。在一些实施方案中,所述化合物对于受试者中的的癌症细胞具有选择性。在一些实施方案中,所述化合物进入对比健康细胞多至少2倍的肿瘤或癌症细胞。在一些实施方案中,癌症是黑色素瘤、脑癌、肺癌、肾上腺癌、肝癌、肾癌或肾癌、胰腺癌、食道癌、胃癌、胃癌、结肠癌、结直肠癌、肛门癌、前列腺癌、卵巢癌、乳腺癌、宫颈癌、淋巴瘤、白血病、骨髓瘤、血癌、肝癌、视网膜母细胞瘤、神经胶质瘤、肉瘤、胚细胞瘤、鳞状细胞癌、腺癌或其组合。在一些实施方案中,所述受试者是人。
本公开提供了其他的方面和实施方案,借由下面详述的记载和附带图示变得显而易见。
附图说明
图1A、图1B、图1C、图1D、图1E是脂筏被标记的肿瘤细胞的图。肿瘤细胞对比正常细胞有更高浓度的脂筏。图1F是正常成纤维细胞和带有CLR 1501(化合物(1))的Caki-2肿瘤细胞图像。CLR1501高度存在于Caki-2细胞中,且最少存在于正常成纤维细胞中。图1G是对照A549细胞的图像,以及图1H是使用甲基b-环糊精处理以破坏脂筏的A549图像。图1G和图1H中的细胞使用CLR1501(化合物(1))培养,然后A549细胞中大多数脂筏的破坏导致CLR1501(化合物(1))摄入降低60%。图1I、图1J和图1K是PC3细胞使用CLR1501(化合物(1))培养并对内质网(ER)进行染色的图像。CLR1501(化合物(1))与ER共同定位于恶性细胞中但不在正常细胞中(未显示)。图1L、图1M和图1N是PC3细胞使用CLR1501(化合物(1))培养并对细胞核和线粒体进行染色的图像。CLR1501(化合物(1))与线粒体共定位。
图2是注射CLR1502(化合物(2))的忍受结直肠(HCT-116)肿瘤的小鼠图像,展示了对肿瘤的定位。
图3是A549(人肺腺癌细胞)或正常人真皮成纤维细胞(NHDF)中,对比缀合至PLE(CLR 1865,化合物)(8))的细胞毒性化合物,细胞毒性相对于细胞毒性化合物(FLV1)的浓度的图。
图4是倍数增加相对于在A375(人黑色素瘤)和HEK293(人胚肾)细胞中PLE缀合物CLR1852(化合物(9))摄入时间随的图。
图5是小鼠中乳腺癌模型的图像,展示CLR1502(化合物(2))的体内摄入。
图6是骨髓瘤细胞系图像,展示了CLR1501(化合物(1))的摄入。
图7是癌症干细胞、正常脑组织和正常干细胞的图像,展示了CLR1501(化合物(1))特定摄入至癌细胞。
图8是对比FLV3,A549(人肺腺癌)细胞和正常人真皮成纤维细胞(NHDF)中,细胞毒性百分比相对于CLR1852(化合物(9))的浓度的图像。
图9是HCT116肿瘤模型中载体对比CLR1852(化合物(9))的肿瘤体积相对于时间的图像。
图10是HCT116肿瘤模型中载体对比CLR1852(化合物(9))的体重相对于时间的图像。
图11是对于在A375(人黑色素瘤)和A549(人肺腺癌)细胞系中细胞溶质(标准化为细胞溶质的体积)中检测到的FLV3的浓度相对于时间的图像。
图12展示了在给药CLR1899(按0.5mg/kg、1mg/kg和2mg/kg)后小鼠模型体重改变的代表性结果。
图13展示了在MCF-7异种移植模型(每剂量组10只小鼠)中CLR1899体内药效的代表性结果。
具体实施方式
本文描述的是磷脂化合物和磷脂-flavagline缀合物。基于多种动物和人体肿瘤中含有高于正常组织中自然发生的醚脂,磷脂醚(PLE)分子被开发出来。本文描述的PLE分子可以用作肿瘤靶向平台来选择性递送药物至肿瘤和癌细胞。
如本文描述,在超过100种不同肿瘤细胞,包括新鲜的人类肿瘤样本中考察了PLE分子的组织分布。PLE分子展示了比正常组织更强的在肿瘤组织中的摄入。PLE分子可与flavagline分子和其衍生物通过连接子缀合,来生成磷脂-flavagline缀合物。
1.定义
除非另有定义,本文所用的所有技术和科学术语具有领域内普通技术人员通常理解的相同含义。在有冲突的情况下,以本文件,包括定义为主导。尽管相似或等价于本文记载的方法和材料可以实践或测试本发明,优选的方法和材料记载如下。本文提到的所有出版物、专利申请、专利和其他引文通过引用的方式全部纳入本文。本文公开的材料、方法和实例仅是说明性的,而不意图限制。
本文所用的术语“包括”、“包含”、“具有”、“有”、“能”、“含”及其变体,意为开放的过渡性短语、术语或词,并不排除添加其他行为或结构的可能。单数形式“一个(a)”,“一个(an)”和“该(the)”包含对其复数的引用,除非语境清楚指明不是这样。本公开也考虑其他实施方案“包含”、“由下列组成”以及“基本由下列组成”本文出现的实施方案和元素,不论是否明示。
本文中为了表示数字范围,明确包含了相同精度的每个间隔数字。例如,对于范围6-9,除了6和9之外数字7和8也考虑在内,以及对于范围6.0-7.0,数字6.0、6.1、6.2、6.3、6.4、6.5、6.6、6.7、6.8、6.9和7.0明确考虑在内。
本文使用的术语“大约”可用于一个或多个有关值,指一个相似于引用值的值。在一些方面,术语“大约”指一个范围内的值落在声明引用值的20%、19%、18%、17%、16%、15%、14%、13%、12%、11%、10%、9%、8%、7%、6%、5%、4%、3%、2%、1%,或更少的某个方向(多于或者少于)内,除非另有声明,或另从上下文中证明(除非这种数字会超过一个可能值的100%)。
具体官能团的定义和化学术语在下面更详细描述。为了本公开的目的,化学元素一致于元素周期表(Periodic Table of the Elements),CAS版本,Handbook ofChemistry and Physics,第75th版,内页,以及特定官能团通常定义为其中所描述的。此外,有机化学的普遍规律和特定功能部分和反应性,记载于Organic Chemistry,ThomasSorrell,University Science Books,Sausalito,1999;Smith and March March'sAdvanced Organic Chemistry,第7版,John Wiley&Sons,Inc.,New York,2013;Larock,Comprehensive Organic Transformations,VCH Publishers,Inc.,New York,1989;Carruthers,Some Modern Methods of Organic Synthesis,第3版,CambridgeUniversity Press,Cambridge,1987;每个的全部内容都以引用的方式全部纳入本文。
如本文所用,术语“烷氧基(alkoxy)”或“烷氧基(alkoxyl)”是指如本文所定义的通过氧原子连接到母体分子部分的烷基。烷氧基的代表性实例包括但不限于甲氧基、乙氧基、丙氧基、2-丙氧基、丁氧基和叔丁氧基。
如本文所用,术语“烷基”是指含有1至20个碳原子的直链或支链饱和烃链。术语“低级烷基”或“C1-6烷基”是指含有1至6个碳原子的直链或支链烃。术语“C1-4烷基”是指含有1至4个碳原子的直链或支链烃。术语“C1-3烷基”是指含有1至3个碳原子的直链或支链烃。烷基的代表性实例包括但不限于甲基、乙基、正丙基、异丙基、正丁基、仲丁基、异丁基、叔丁基、正戊基、异戊基、新戊基、正-己基、3-甲基己基、2,2-二甲基戊基、2,3-二甲基戊基、正庚基、正辛基、正壬基和正癸基。
如本文所用,术语“烯基”是指含有2至20个碳原子和至少一个碳-碳双键的不饱和烃链。
如本文所用,术语“炔基”是指含有2至20个碳原子和至少一个碳-碳三键的不饱和烃链。
如本文所用,术语“烷氧基烷基”是指通过如本文所定义的亚烷基连接至母体分子部分的如本文所定义的烷氧基。
如本文所用,术语“芳基烷基”是指通过如本文所定义的亚烷基连接至母体分子部分的如本文所定义的芳基。
如本文所用,术语“烷基氨基”是指至少一个如本文所定义的烷基通过如本文所定义的氨基连接至母体分子部分。
如本文所用,术语“亚烷基”是指衍生自1至10个碳原子如2至5个碳原子的直链或支链烃的二价基团。亚烷基的代表性实例包括但不限于-CH2CH2-、-CH2CH2CH2-、-CH2CH2CH2CH2-,和–CH2CH2CH2CH2CH2-。
如本文所用,术语“酰胺”是指-C(O)NR-或-NRC(O)-,其中R可以是氢、烷基、环烷基、芳基、杂芳基、杂环、烯基或杂烷基。
如本文所用,术语“氨基烷基”是指至少一个如本文所定义的氨基通过如本文所定义的亚烷基连接至母体分子部分。
如本文所用,术语“氨基”是指-NRxRy,其中Rx和Ry可以是氢、烷基、环烷基、芳基、杂芳基、杂环、烯基或杂烷基。在氨基烷基或其中氨基将两个其他部分连接在一起的任何其他部分的情况下,氨基可以是-NRx-,其中Rx可以是氢、烷基、环烷基、芳基、杂芳基、杂环、烯基或杂烷基。
如本文所用,术语“芳基”是指芳族基团,例如苯基,或双环稠环体系。双环稠合环系统的例子是将苯基连接到母体分子部分并稠合到如本文所定义的环烷基、苯基、如本文所定义的杂芳基或如本文所定义的杂环。芳基的代表性实例包括但不限于吲哚基、萘基、苯基、喹啉基和四氢喹啉基。“芳基烷基”是指如本文所定义的烷基被芳基取代。
“亚芳基”是指如本文所定义的芳基,其具有通过从母体芳基的两个不同碳原子上除去两个氢原子而衍生的两个单价基团中心。典型的亚芳基包括但不限于亚苯基和亚萘基。“芳基亚烷基”是指如本文所定义的芳基烷基,其具有两个单价基团中心,该中心通过从该基团的芳基中除去一个氢原子和从该基团的烷基中除去另一个氢而衍生。
如本文所用,术语“羧基”是指羧酸或-COOH。
术语“环烷基”是指一价饱和烃环或双环基团。环烷基具有零个杂原子和零个双键。环烷基是单环的,或者是稠合的、螺环的或桥接的双环系统。单环环烷基在环中含有3-10个碳原子,优选4-7个碳原子,更优选5-6个碳原子。双环环烷基在环中含有8至12个碳原子,优选9至10个碳原子。环烷基可以是取代的或未取代的。环烷基包括例如环丙基、环丁基、环戊基、环己基和环庚基。
如本文所用,术语“环烯基”是指包含至少一个碳-碳双键并且优选每个环具有5-10个碳原子的非芳族单环或多环环系统。示例性的单环环烯基环包括环戊烯基、环己烯基和环庚烯基。
如本文所用,术语“环炔基”是指含有至少一个碳-碳三键并且优选具有每环5-10个碳原子或每环超过10个碳原子的单环或多环环系统。
如本文所用,术语“卤代烷基”是指如本文所定义的烷基,其中一个、两个、三个、四个、五个、六个、七个或八个氢原子被卤素取代。卤代烷基的代表性实例包括但不限于2-氟乙基、2,2,2-三氟乙基、三氟甲基、二氟甲基、五氟乙基和三氟丙基例如3,3,3-三氟丙基。
如本文所用,术语“卤素”或“卤代”是指Cl、Br、I或F。
如本文所用,术语“杂烷基”是指如本文所定义的烷基,其中所述烷基的至少一个碳被杂原子如氧、氮和硫取代。杂烷基的代表性实例包括但不限于烷基醚、仲烷基胺和叔烷基胺、酰胺和烷基硫醚。
如本文所用,术语“杂芳基”是指包含至少一个独立地选自N、O和S的杂原子的芳族单环或芳族双环系统。芳族单环是包含至少一个独立地选自由N、O和S组成的组的杂原子的五或六元环。五元芳族单环具有两个双键并且六元六元芳族单环具有三个双键。双环杂芳基的例子是连接到母体分子部分并稠合到如本文所定义的单环环烷基、如本文所定义的单环芳基、如本文所定义的单环杂芳基或如本文所定义的单杂环的单环杂芳基环。杂芳基的代表性实例包括但不限于吲哚基、吡啶基(包括吡啶-2-基、吡啶-3-基、吡啶-4-基)、嘧啶基、吡嗪基、哒嗪基、吡唑基、吡咯基、苯并吡唑基、1,2,3-三唑基、1,3,4-噻二唑基、1,2,4-噻二唑基、1,3,4-恶二唑基、1,2,4-恶二唑基、咪唑基、噻唑基、异噻唑基、噻吩基、苯并咪唑基、苯并噻唑基、苯并恶唑基、苯并恶二唑基、苯并噻吩基、苯并呋喃基、异苯并呋喃基、呋喃基、恶唑基、异恶唑基、嘌呤基、异吲哚基、喹喔啉基(quinoxalinyl)、吲唑基、喹唑啉基、1,2,4-三嗪基、1,3,5-三嗪基、异喹啉基、喹啉基、6,7-二氢-1,3-苯并噻唑基、咪唑并[1,2-a]吡啶基、萘啶基、吡啶并咪唑基、噻唑并[5,4-b]吡啶-2-基、噻唑并[5,4-d]嘧啶-2-基。
如本文所用,术语“杂环”或“杂环的”或“杂环基”是指单环杂环、双环杂环(heterobicyclic)或三环杂环。单环杂环是包含至少一个独立地选自由O、N和S组成的组的杂原子的三元、四元、五元、六元、七元或八元环。三元环或四元环含有0个或1个双键和1个选自由O、N和S组成的组的杂原子。五元环含有0个或1个双键和1个、2个或3个选自由O、N和S组成的组的杂原子。六元环包含0、1或2个双键和1、2或3个选自由O、N和S组成的组的杂原子。七元和八元环包含零个、一个、两个或三个双键和一个、两个或三个选自由O、N和S组成的组的杂原子。单环杂环的代表性实例包括但不限于吖丁啶基、氮杂环庚烷基(azepanyl)、氮丙啶基、二氮杂环庚烷基(diazepanyl)、1,3-二恶烷基、1,3-二氧戊环基、1,3-二硫杂环戊烷基(dithiolanyl)、1,3-二噻烷基(1,3-dithianyl)、咪唑啉基(imidazolinyl)、咪唑烷基、异噻唑啉基、异噻唑烷基、异恶唑啉基、异恶唑烷基、吗啉基、恶二唑啉基、恶二唑烷基、恶唑啉基、恶唑烷基、氧杂环丁烷基、哌嗪基、哌啶基、吡喃基、吡唑啉基、吡唑烷基、吡咯啉基、吡咯烷基、四氢呋喃基、四氢吡喃基、四氢吡啶基、四氢噻吩基、噻二唑啉基、噻二唑烷基、1,2-噻嗪基(1,2-thiazinanyl)、1,3-噻嗪基(1,3-thiazinanyl)、噻唑啉基(thiazolinyl)、噻唑烷基(thiazolidinyl)、硫代吗啉基(thiomorpholinyl)、1,1-二氧化硫代吗啉基(1,1-dioxidothiomorpholinyl)(硫代吗啉砜)、噻喃基(thiopyranyl)和三硫杂环己烷基(trithianyl)。双环杂环是单环杂环与苯基稠合,或单环杂环与单环环烷基稠合,或单环杂环与单环环烯基稠合,或单环杂环与单环杂环稠合,或桥接的单环杂环的环系统,其中环的两个不相邻原子通过1、2、3或4个碳原子的亚烷基桥或2、3或4个碳原子的亚烯基桥连接。双环杂环的代表性实例包括但不限于,苯并吡喃基、苯并噻喃基(benzothiopyranyl)、苯并二氢吡喃基(chromanyl)、2,3-二氢苯并呋喃基、2,3-二氢苯并噻吩基、2,3-二氢异喹啉、氮杂双环[2.2.1]庚基(包括2-氮杂双环[2.2.1]庚-2-基)、2,3-二氢-1H-吲哚基、异二氢氮茚基(isoindolinyl)、八氢环戊[c]吡咯基、八氢吡咯并吡啶基和四氢异喹啉基。三环杂环的例子有双环杂环与苯基稠合,或双环杂环与单环环烷基稠合,或双环杂环与单环环烯基稠合,或双环杂环与单环杂环稠合,或双环杂环其中的的双环的两个不相邻原子通过1、2、3或4个碳原子的亚烷基桥,或2、3或4个碳原子的亚烯基桥连接。三环杂环的实例包括但不限于八氢-2,5-环氧戊烷、六氢-2H-2,5-甲环戊[b]呋喃(hexahydro-2H-2,5-methanocyclopenta[b]furan)、六氢-1H-1,4-甲环戊[c]呋喃(hexahydro-1H-1,4-methanocyclopenta[c]furan)、氮杂金刚烷(1-氮杂三环[3.3.1.13,7]癸烷)和氧杂金刚烷(2-氧杂三环[3.3.1.13,7]癸烷)。单环、双环和三环杂环通过环内包含的任何碳原子或任何氮原子连接到母体分子部分,并且可以是未取代的或取代的。
如本文所用,术语“杂芳基烷基”是指通过如本文所定义的亚烷基与母体分子部分连接的如本文所定义的杂芳基。
如本文所用,术语“杂环基烷基”是指通过如本文所定义的亚烷基连接至母体分子部分的如本文所定义的杂环基团。
如本文所用,术语“羟基(hydroxyl)”或“羟基(hydroxy)”是指-OH基团。
如本文所用,术语“羟基烷基”是指至少一个-OH基团,通过如本文所定义的亚烷基连接至母体分子部分。
在一些情况下,烃基取代基(例如烷基或环烷基)中的碳原子数由前缀“Cx-y-”表示,其中x是取代基中最小碳原子数并且y是取代基中的E最大碳原子数。因此,例如,“C1-3烷基”是指含有1至3个碳原子的烷基取代基。
术语“取代的”是指可以被一个或多个非氢取代基进一步取代的基团。取代基包括但不限于卤素、=O(氧代)、=S(硫代)、氰基、硝基、氟代烷基、烷氧基氟代烷基、氟代烷氧基、烷基、烯基、炔基、卤代烷基、卤代烷氧基、杂烷基、环烷基、环烯基、芳基、杂芳基、杂环、环烷基烷基、杂芳基烷基、芳基烷基、羟基、羟烷基、烷氧基、烷氧基烷基、亚烷基、芳氧基、苯氧基、苄氧基、氨基、烷基氨基、酰基氨基、氨基烷基、芳基氨基、磺酰基氨基、亚磺酰基氨基、磺酰基、烷基磺酰基、芳基磺酰基、氨基磺酰基,亚磺酰基、-COOH、酮、酰胺、氨基甲酸基(carbamate)和酰基。
对于本文所述的化合物,其基团和取代基可以根据原子和取代基的允许的化合价来选择,使得选择和取代产生稳定的化合物,例如,其不会自发地经历转化,例如通过重排、环化、消除等。
如本文所用,术语“施用”或“施用”是指通过任何合适的途径提供、接触和/或递送化合物或缀合物以实现期望的效果。这些化合物或缀合物可以以多种方式施用于受试者,包括但不限于口服、经眼、经鼻、静脉内、局部、作为气雾剂、栓剂等,并且可以组合使用。
如本文所用,“癌症”可包括源自肿瘤、赘生物、癌症、癌前病变、细胞系、恶性肿瘤的任何细胞或组织,或具有无限扩增和生长潜力的任何其他细胞来源。癌细胞可能来自天然来源,也可能是人工产生的。癌细胞也可能能够侵入其他组织和转移。癌细胞进一步包括已经侵入其他组织和/或转移的任何恶性细胞。在生物体的上下文中的一种或多种癌细胞也可以称为癌症、肿瘤、赘生物、生长、恶性肿瘤或本领域中用于描述处于癌变状态的细胞的任何其他术语。癌症可包括例如黑色素瘤、脑癌、肺癌、肾上腺癌、肝癌、肾癌或肾癌、胰腺癌、食道癌、胃癌、胃癌、结肠癌、结直肠癌、肛门癌、前列腺癌、卵巢癌、乳腺癌、宫颈癌、淋巴瘤、白血病、骨髓瘤、血癌、肝癌、视网膜母细胞瘤、神经胶质瘤、肉瘤、胚细胞瘤、鳞状细胞癌和腺癌
如本文所用,术语“癌症干细胞”是指能够自我更新和分化成在恶性肿瘤中发现的不同类型的癌细胞的癌细胞。
一般而言,提及“循环肿瘤细胞”(CTC)旨在指单个细胞,而提及“循环肿瘤细胞”或“循环肿瘤细胞簇”旨在指多于一个的癌细胞。然而,本领域技术人员将理解,提及“循环肿瘤细胞”旨在包括循环肿瘤细胞群,包括一种或多种循环肿瘤细胞,而提及“循环肿瘤细胞”可包括多于一种循环肿瘤细胞。如本文所用,术语“循环肿瘤细胞”或“循环肿瘤细胞”是指在受试者的血液或血清样品中发现的任何癌细胞或癌细胞簇。CTC还可以包含或由在受试者的血液或血清样品中发现的癌症干细胞或癌症干细胞簇组成。
本文使用的术语“对照”、“参考水平”和“参照”可相互替换。参考水平可以是预定的值或范围,用来作为评估测量结果的标准。本文使用的“对照组”指一组对照受试者。预定的水平可以是对照组的截止值。预定水平可以是对照组的平均值。截止值(或预定截止值)可以使用自适应指数模型(AIM)方法测定。截止值(或预定截止值)可以由患者组的生物样品的接受者操作曲线(ROC)分析中确定。ROC分析,为生物领域普遍已知的,是区分一种情况与另一种情况的能力的测试确定方法。ROC分析的描述见于P.J.Heagerty等人(Biometrics2000,56,337-44),其公开在此以引用的方式全部纳入本文。或者,截止值通过患者组生物样品的四分区分析。例如,截止值例如,可以通过选择对应于第25-75个百分位范围内的任何值的值来确定截止值,优选地,对应于第25个百分位、第50个百分位或第75个百分位的值,更优选地,第75个百分位的值。这样的统计分析可以使用本领域已知的任何方法来执行,并且可以通过任何数量的可市购的软件包来实现(例如来自Analyse-it SoftwareLtd.,Leeds,UK;StataCorp LP,College Station,TX;SAS Institute Inc.,Cary,NC.)。靶标或对于蛋白活动的健康或正常的水平或范围可以根据标准操作定义。对照可以是受试者,或来自受试者的样品,所述的受试者的疾病状况是已知的。受试者或来自受试者的样品,可以是健康的、患病的、患病在治疗前、治疗期间患病、治疗后患病或治疗后健康或其组合。如本文所用,术语“正常受试者”是指健康受试者,即没有疾病临床体征或症状的受试者。对正常受试者进行临床评估以发现其他未检测到的疾病体征或症状,该评估可包括常规身体检查和/或实验室测试。在一些实施方案中,对照是健康对照。在一些实施方案中,对照包括癌症。
如本文所用,术语“有效剂量”或“治疗剂量”或“治疗有效量”或“有效量”是指足以引起治疗效果的量或在必要时间段内有效的药物剂量,以达到预期的治疗效果。有效剂量可由本领域技术人员确定,并可根据个体的疾病状态、年龄、性别和体重、给药方式、疾病的阶段和严重程度、受试者一般健康情况等因素而变化、处方医师的判断以及药物在个体中引起所需反应的能力而变化。治疗有效量也是一种考虑其中物质的任何毒性或有害作用被治疗有益作用所超过的量。“预防有效量”是指在必要的剂量和时间段内有效达到所需预防结果的量。通常,由于在疾病之前或疾病早期在受试者中使用预防剂量,因此预防有效量将小于治疗有效量。
术语“抑制”或“抑制”是指在抑制剂存在时活性降低或阻止,与在抑制剂不存在时相反。术语“抑制”是指过程的减少或下调或对过程中刺激的消除,这导致生物标志物或多肽的表达或活性不存在或最小化。抑制可以是直接的或间接的。抑制可能是特异性的,即抑制剂抑制某种生物标志物或多肽而不是其他。
如本文所用的“样品”或“测试样品”可以指其中化合物或靶标的存在和/或水平是要检测或确定的任何样品。样品可能包括液体、溶液、乳液、混合物或悬浮液。样品可以包括医学样品。样品可以包括任何生物体液或组织,例如血液、全血、血液部分例如血浆和血清、外周血单核细胞(PBMC)、肌肉、间质液、汗液、唾液、尿液、泪液、滑液、骨骼骨髓、脑脊液、鼻分泌物、痰液、羊水、支气管肺泡灌洗液、洗胃液、呕吐物、粪便、肺组织、外周血单个核细胞、总白细胞、淋巴结细胞、脾细胞、扁桃体细胞、癌细胞、肿瘤细胞、胆汁、消化液、皮肤或其组合。在一些实施方案中,样品包括等分试样。在其他实施例中,样品包括生物流体。样品可以通过本领域已知的任何方式获得。样品可以直接使用从患者获得的样品,也可以进行预处理,例如通过过滤、蒸馏、提取、浓缩、离心、干扰成分的灭活、添加试剂等,以本文讨论的某种方式或本领域已知的其他方式,以改变样品的性质。样品可以在诊断前、治疗前、治疗期间、治疗后或诊断后或其组合中获得。
本文使用的术语“特异性”是指真阴性的数量除以真阴性的数量加上假阳性的数量,其中特异性(“spec”)可以在0<spec<1的范围内。因此,优选灵敏度和特异性均等于1或100%的方法。
“特异性结合”通常是指当化合物或缀合物与靶标结合比它与随机的、不相关的靶标结合时更容易与靶标结合。
如本文所用的“受试者”可以指想要或需要本文描述的化合物或方法的哺乳动物。受试者可以是人类或非人类动物。受试者可以是哺乳动物。哺乳动物可以是灵长类或非灵长类。哺乳动物可以是灵长类动物,例如人;非灵长类动物,例如狗、猫、马、牛、猪、小鼠、大鼠、骆驼、美洲驼、山羊、兔、绵羊、仓鼠和豚鼠;或非人类灵长类动物,例如猴子、黑猩猩、大猩猩、猩猩和长臂猿。受试者可以是任何年龄或发育阶段,例如成人、青少年或婴儿。受试者可以是男性或女性。在一些实施方案中,受试者具有特定的遗传标记。
如本文所用,术语“有毒”是指对受试者有害或引起任何不利影响的化学实体、试剂或物质的量。术语“无毒”是指对受试者造成损害的程度相对较低的物质。“细胞毒性”是指对细胞有毒的化学实体、试剂或物质。毒性可以指对整个生物体如动物、细菌、植物或本文定义的其他受试者的影响,以及对生物体亚结构如细胞(细胞毒性)或器官(器官毒性),例如肝脏(肝毒性)的影响。毒理学的一个核心概念是影响是剂量依赖性的。即使是水,在摄入足够大的剂量时也会导致水中毒,而即使对于像蛇毒这样的毒性很大的物质,在低于该剂量时也不会检测到毒性作用。相对无毒的组合物或化合物可以允许更广泛的受试者能够安全地处理组合物或化合物,而没有严重的安全问题或风险。
如本文所用的术语“治疗(treat)”、“治疗(treated)”或“治疗(treating)”是指治疗剂,其中目的是减缓(减轻)不希望的生理状况、障碍或疾病,或获得有益的或希望的临床结果。为了本发明的目的,有益的或期望的临床结果包括但不限于症状的缓解;减轻病症、紊乱或疾病的程度;病情、紊乱或疾病状态的稳定(即不恶化);延缓病情、紊乱或疾病的发作或进展减缓;改善病情、紊乱或疾病状态;和缓解(无论是部分的还是全部的),无论是可检测的还是不可检测的,或者病情、紊乱或疾病的增强或改善。治疗还包括与未接受治疗的预期生存期相比延长生存期。“治疗(Treatment)”或“治疗(treating)”在提及保护受试者免受疾病时,意指抑制、压制、改善或完全消除疾病。预防疾病包括在疾病发作之前向受试者施用本发明的组合物。抑制疾病包括在疾病诱发之后但在其临床出现之前向受试者施用本发明的组合物。压制或改善疾病包括在疾病出现临床表现后将本发明的组合物施用于受试者。该疾病可以包括癌症。
2.磷脂醚
本文提供了磷脂醚(PLE)分子。PLE可以根据式(I')或其盐:
其中X是氢、甲基或被羧基取代的苯基。
在一些实施例中,PLE选自以下:
PLE可以缀合至可检测部分(也称为报告物或标记物),例如荧光分子、化学发光分子、放射性标记、磁性标记、红外分子或其组合。磁性标记是标记部分,当其与磁性接近传感器充分结合时,可被磁性接近传感器检测并导致磁性接近传感器输出信号。磁性标记可包括一种或多种选自顺磁性、超顺磁性、铁磁性、铁磁性、反铁磁性材料、它们的组合等的材料。荧光标记是可被荧光检测器检测到的标记部分。合适的荧光分子(荧光团)包括但不限于荧光素、异硫氰酸荧光素、羧基荧光素的琥珀酰亚胺酯、荧光素的琥珀酰亚胺酯、荧光素二氯三嗪的5-异构体、笼状羧基荧光素-丙氨酸-甲酰胺、俄勒冈绿488、俄勒冈绿514;路西法黄、吖啶橙、罗丹明、四甲基罗丹明、德克萨斯红、碘化丙啶、JC-1(5,5',6,6'-四氯-1,1',3,3'-四乙基苯并咪唑基羰花青碘化物)、四溴罗丹明123、罗丹明6G、TMRM(四甲基罗丹明甲酯)、TMRE(四甲基罗丹明乙酯)、四甲基亚硝基氨(tetramethylrosamine)、罗丹明B和4-二甲氨基四甲基亚硝基氨(4-dimethylaminotetramethylrosamine)、绿色荧光蛋白、蓝移绿色荧光蛋白、青色移绿色荧光蛋白、红移绿色荧光蛋白、黄移绿色荧光蛋白、4-乙酰氨基-4'-异硫氰酸芪-2,2'二磺酸(4-acetamido-4’-isothiocyanatostilbene-2,2’disulfonicacid);吖啶及其衍生物,如吖啶、异硫氰酸吖啶;5-(2'-氨基乙基)氨基萘-1-磺酸(EDANS);4-氨基-N-[3-乙烯基磺酰基)苯基]萘甲酰胺-3,5二磺酸盐(4-amino-N-[3-vinylsulfonyl)phenyl]naphtha-alimide-3,5disulfonate);N-(4-苯胺基-1-萘基)马来酰亚胺;邻氨基苯甲酰胺(anthranilamide);4,4-二氟-5-(2-噻吩基)-4-bora-3a,4adiaza-5-茚满-3-丙酸BODIPY(4,4-difluoro-5-(2-thienyl)-4-bora-3a,4a diaza-5-indacene-3-propionic acid BODIPY);级联蓝色;亮黄色;香豆素及其衍生物:香豆素、7-氨基-4-甲基香豆素(AMC、香豆素120)、7-氨基-4-三氟甲基香豆素(香豆素151);花青染料;四氯四溴荧光素(cyanosine);4',6-二脒基-2-苯基吲哚(4’,6-diaminidino-2-phenylindole)(DAPI);5′,5″-二溴代焦酚磺萘(5′,5″-dibromopyrogallol-sulfonaphthalein)(溴焦酚红);7-二乙氨基-3-(4'-异硫氰酰苯基)-4-甲基香豆素(7-diethylamino-3-(4’-isothiocyanatophenyl)-4-methylcoumarin);二亚乙基三胺五乙酸酯;4,4'-二异硫氰基二氢芪-2-,2'-二磺酸(4,4’-diisothiocyanatodihydro-stilbene-2,2’-disulfonic acid);4,4'-二异硫氰基芪-2,2'-二磺酸(4,4’-diisothiocyanatostilbene-2,2’-disulfonic acid);5-(二甲氨基)萘-1-磺酰氯(DNS,丹磺酰氯);4-二甲基氨基苯基偶氮苯基-4'-异硫氰酸酯(DABITC);曙红及其衍生物:曙红、曙红异硫氰酸酯、赤藓红及其衍生物:赤藓红B、赤藓红、异硫氰酸酯;乙啡啶;荧光素及其衍生物:5-羧基荧光素(FAM)、5-(4,6-二氯三嗪-2-基)氨基-1-荧光素(5-(4,6-dichlorotriazin-2-yl)amino-1-fluorescein)(DTAF)、2',7'二甲氧基-4'5'-二氯-6-羧基荧光素(JOE)、荧光素、异硫氰酸荧光素、QFITC、(XRITC);荧光胺;IR144;IR1446;孔雀绿异硫氰酸酯;4-甲基伞形酮邻甲酚酞(4-methylumbelli-feroneortho cresolphthalein);硝基酪氨酸;副蔷薇胺;酚红;B-藻红蛋白;邻苯二甲醛;芘及其衍生物:芘、丁酸芘、琥珀酰亚胺基1-芘;丁酸量子点;Reactive Red4(CibacronTM Brilliant Red 3B-A)罗丹明及其衍生物:6-羧基-X-罗丹明(ROX)、6-羧基罗丹明(R6G)、丽丝胺罗丹明B磺酰氯罗丹明(Rhod)、罗丹明B、罗丹明123、罗丹明X异硫氰酸酯、磺基罗丹明B、磺基罗丹明101、磺基罗丹明101(德克萨斯红)的磺酰氯衍生物;N,N,N',N'-四甲基-6-羧基罗丹明(TAMRA);四甲基罗丹明;四甲基胡丹明异硫氰酸酯(TRITC);核黄素;5-(2'-氨基乙基)氨基萘-1-磺酸(EDANS)、4-(4'-二甲基氨基苯基偶氮)苯甲酸(DABCYL)、玫红酸;CAL荧光橙560;铽螯合物的衍生物;CY3;CY 5;Cy5.5;Cy 7;IRD 700;IRD 800;拉霍亚蓝;酞菁;和萘酞菁、香豆素和相关染料,氧杂蒽染料如对甲氨基酚(rhodols)、试卤灵、bimanes、吖啶、异吲哚、丹磺酰基染料,胺基苯二甲酰肼(aminophthalic hydrazides)如鲁米诺,以及异鲁米诺衍生物、氨基邻苯二甲酰亚胺、氨基萘酰亚胺、氨基苯并呋喃、氨基喹啉、二氰基氢醌、荧光铕和铽的复合物;其组合等。
可检测部分可以共价或可切割地连接到PLE。例如,标记的PLE可以从以下选项中选择:
上述化合物(1)是具有与PLE稳定连接的荧光部分BODIPY的PLE(3),也可称为CLR1501。上述化合物(2)是具有与PLE稳定连接的近红外分子IR-775的PLE(3),也可称为CLR 1502。化合物(1)和(2)也可称为磷脂药物缀合物(PDC)。
PLE或其缀合物可以对肿瘤或癌细胞具有特异性。在施用于受试者后,PLE或其缀合物可定位于肿瘤或癌细胞。PLE或其缀合物可以掺入比健康细胞更多的肿瘤或癌细胞中。PLE或其缀合物可掺入的肿瘤或癌细胞比健康细胞多至少约2倍、至少约3倍、至少约4倍、至少约5倍、至少约6倍、至少约7倍、至少约8倍、至少约9倍、至少约10倍、至少约15倍、至少约20倍、至少约25倍、至少约30倍。
3.磷脂flavagline缀合物化合物
PLE可通过连接子与flavagline化合物缀合以形成磷脂-flavagline缀合物(也称为PLE-flavagline缀合物)。
在一方面,本申请提供了式(I)的化合物或其药学可接受的盐,
其中Z是flavagline类似物。
Flavagline是在Aglaia(楝科)的植物中发现的天然产物家族。Flavagline的特点是具有环戊二[b]苯并呋喃骨架。Flavagline类化合物可能具有很强的杀虫、抗真菌、抗炎、神经保护、心脏保护和抗癌活性。Flavagline可以增强化学疗法的功效和/或减轻化学疗法的心脏副作用。合适的flavagline类似物包括,例如,美国专利申请公开US 2018/0086729中公开的化合物,其内容通过引用整体并入本文。Flavagline类化合物可以包括,例如,FLV1、FLV3、其衍生物或结构类似物,或它们的组合。如本文所用,术语“flavagline类似物”或“flavagline抗癌药”包括所有天然和合成的flavagline化合物、其衍生物及其结构类似物。
在一些实施方案中,flavagline类似物包含FLVl,或其盐:
在一些实施方案中,flavagline类似物包含FLV3,或其盐:
如本文所公开的合适化合物包括:
(CLR 1899),和
或其药学可接受的盐。
在一些实施方案中,化合物是
(CLR 1899),或其药学可接受的盐。
还提供了式(II)的缀合物或其盐:
在式(II)中,连接子可以是可切割的连接子,例如二硫化物,并且专门设计用于将flavagline递送至肿瘤或癌细胞。在一些实施方案中,连接子包含二硫化物。在一些实施方案中,连接子包括以下:
在一些实施方案中,式(II)的磷脂-flavagline缀合物选自以下,或其药学可接受的盐:
CLR 1865(带FLV1)(8),和
CLR 1852(带FLV3)(9)。
如本文所述的化合物可以作为立体异构体存在,其中存在不对称或手性中心。立体异构体是“R”或“S”,取决于手性碳原子周围的取代基的构型。此处使用的术语“R”和“S”是IUPAC 1974Recommendations for Section E,Fundamental Stereochemistry,PureAppl.Chem.,1976,45,13-30中定义的构型。本公开内容涵盖了各种立体异构体及其混合物,并且这些具体包括在本发明的范围内。立体异构体包括对映异构体和非对映异构体,以及对映异构体或非对映异构体的混合物。化合物的单个立体异构体可以由含有不对称或手性中心的市售起始材料合成制备,或通过制备外消旋混合物然后采用本领域普通技术人员熟知的拆分方法制备。这些拆分方法的例子包括(1)将对映异构体混合物连接到手性助剂,通过重结晶或色谱法分离所得非对映异构体混合物,以及可选地从助剂中释放光学纯产物,如记载于Furniss,Hannaford,Smith和Tatchell,“Vogel's Textbook of PracticalOrganic Chemistry”,第5版(1989年),Longman Scientific&Technical,Essex CM20 2JE,英格兰,或(2)在手性色谱柱上直接分离光学对映异构体混合物,或(3)分级再结晶法。应当理解,本文所述的化合物可以包括互变异构形式以及几何异构体,并且这些异构体也构成本公开的实施方案。如本文所述的化合物可以作为外消旋混合物存在。
本发明还包括同位素标记的化合物,例如同位素标记的PLE、同位素标记的flavagline、同位素标记的连接子或同位素标记的磷脂-flavagline缀合物。同位素标记的化合物与本文详述的化合物相同除了一个或多个原子被原子质量或质量数不同于自然界中通常发现的原子质量或质量数的原子取代。适合包含在本发明化合物中的同位素的实例是氢、碳、氮、氧、磷、硫、氟和氯,分别例如但不限于2H、3H、13C、14C、15N、18O、17O、31P、32P、35S、18F和36Cl。用较重的同位素例如氘,即2H,进行取代可以提供某些治疗优势,这些优势源于更高的代谢稳定性,例如体内半衰期增加或剂量要求降低,因此在某些情况下可能是优选的。该化合物可以包含正电子发射同位素用于医学成像和用于确定受体分布的正电子发射断层扫描(PET)研究。可掺入化合物中的合适的正电子发射同位素是11C、13N、15O和18F。同位素标记的化合物通常可以通过本领域技术人员已知的常规技术或通过与所附实施例中描述的那些类似的方法使用合适的同位素标记的试剂代替非同位素标记的试剂来制备。
公开的PLE或磷脂-flavagline缀合物可按药学可接受的盐存在。术语“药学可接受的盐”指化合物的盐或两性离子,其是水溶的或油溶的或可分散的,适合治疗障碍而没有过度毒性,刺激和过敏反应,与合理的收益/风险比相称,并对其预期用途有效。盐可以在化合物的最终分离和纯化过程中制备,或单独通过使化合物的氨基与合适的酸反应来制备。例如,化合物可以溶解在合适的溶剂中,例如但不限于甲醇和水,并用至少一当量的酸例如盐酸处理。所得盐可沉淀出来并通过过滤分离并在减压下干燥。或者,可在减压下除去溶剂和过量酸以提供盐。代表性的盐包括乙酸盐、己二酸盐、藻酸盐、柠檬酸盐、天冬氨酸盐、苯甲酸盐、苯磺酸盐、硫酸氢盐、丁酸盐、樟脑酸盐、樟脑磺酸盐、二葡萄糖酸盐、甘油磷酸盐、半硫酸盐、庚酸盐、己酸盐、甲酸盐、羟乙基磺酸盐、富马酸盐、乳酸盐、马来酸盐、甲磺酸盐、萘磺酸盐、烟酸盐、草酸盐、双羟萘酸盐、果胶酸盐、过硫酸盐、3-苯基丙酸盐、苦味酸盐、草酸盐、马来酸盐、新戊酸盐、丙酸盐、琥珀酸盐、酒石酸盐、三氯乙酸盐、三氟乙酸盐、谷氨酸盐、对甲苯磺酸盐、十一烷酸盐、盐酸、氢溴酸、硫酸、磷酸等。化合物的氨基也可以用烷基氯化物、溴化物和碘化物例如甲基、乙基、丙基、异丙基、丁基、月桂基、肉豆蔻基、硬脂基等进行季铵化。
碱性加成盐可在公开的化合物的最终分离和纯化过程中通过羧基与合适的碱如金属阳离子如锂、钠、钾、钙、镁或铝的氢氧化物、碳酸盐或碳酸氢盐的反应来制备,或有机伯胺、仲胺或叔胺。可以制备季胺盐,例如衍生自甲胺、二甲胺、三甲胺、三乙胺、二乙胺、乙胺、三丁胺、吡啶、N,N-二甲基苯胺、N-甲基哌啶、N-甲基吗啉、二环己胺、普鲁卡因、二苄胺、N,N-二苄基苯乙胺、1-苯乙胺(1-ephenamine)和N,N'-二苄基乙二胺、乙二胺、乙醇胺、二乙醇胺、哌啶、哌嗪等。
如本文所述的磷脂-flavagline缀合物化合物可以对肿瘤或癌细胞具有特异性。在施用于受试者后,化合物可定位于肿瘤或癌细胞。这些化合物可以定位或移动到肿瘤或癌细胞的细胞质或细胞器。,这些化合物可以掺入与健康细胞相比更多的肿瘤或癌细胞中。可以将化合物掺入比健康细胞至少约2倍、至少约3倍、至少约4倍、至少约5倍、至少约6倍、至少约7倍、至少约8倍、至少约9倍、至少约10倍、至少约15倍、至少约20倍、至少约25倍、至少约30倍的肿瘤或癌症细胞。
可以从本发明的化合物中裂解flavagline或flavagline类似物,例如在对受试者给药后在体内裂解。Flavagline或flavagline类似物可定位或行进至肿瘤或癌细胞的细胞质或细胞器。Flavagline或flavagline类似物可以掺入与健康细胞相比更多的肿瘤或癌细胞中。Flavagline或flavagline类似物可掺入比健康细胞至少约2倍、至少约3倍、至少约4倍、至少约5倍、至少约6倍、至少约7倍至少约8倍、至少约9倍、至少约10倍、至少约15倍、至少约20倍、至少约25倍、至少约30倍以上的肿瘤或癌细胞。
如本文所述的化合物可根据实施例1中所述的方法或本领域已知的其他方法合成。合成过程可以包括制备PLE部分、flavagline类似物部分和如实施例1所示的完整化合物的步骤。合适的flavagline包括市售产品,例如来自Haoyuan Chemexpress Co.(中国上海)的那些。
4.药物组合物
本文所述的化合物或其药学上可接受的盐可以根据制药领域技术人员熟知的标准技术配制成药物组合物。在一个方面,本公开提供了一种包含如本文所述的化合物、或其药学可接受的盐和药学上可接受的载体的药物组合物。如本文所用,术语“药学上可接受的载体”是指任何类型的无毒、惰性固体、半固体或液体填充剂、稀释剂、包封材料或制剂助剂。
本发明化合物的给药途径和组合物的形式将决定所用载体的类型。药物组合物可以是多种形式,例如适用于全身给药(例如,口服、直肠、舌下、口腔、植入物、鼻内、阴道内、透皮、静脉内、动脉内、瘤内、腹膜内或肠胃外)或局部给药(例如,皮肤、肺、鼻、耳、眼、脂质体递送系统或离子电渗疗法)。在一些实施方案中,药物组合物用于施用于受试者的中枢神经系统。技术和配方通常可以在“Remington's Pharmaceutical Sciences”(MeadePublishing Co.,Easton,Pa.)中找到。药物组合物在制造和储存条件下通常必须是无菌且稳定的。所有载体在组合物中都是可选的。
药学上可接受的载体包括例如稀释剂、润滑剂、粘合剂、崩解剂、着色剂、调味剂、甜味剂、抗氧化剂、防腐剂、助流剂、溶剂、助悬剂、润湿剂、表面活性剂、润肤剂、推进剂、保湿剂、粉末、pH调节剂及其组合。
可用作药学上可接受的载体的材料的一些实例包括但不限于离子交换剂、氧化铝、硬脂酸铝、卵磷脂、血清蛋白(如人血清白蛋白)、缓冲物质(如磷酸盐)、甘氨酸、山梨酸或山梨酸钾、饱和植物脂肪酸的部分甘油酯混合物、水、盐或电解质(如硫酸鱼精蛋白、磷酸氢二钠、磷酸氢钾、氯化钠、锌盐)、胶体二氧化硅、三硅酸镁、聚乙烯吡咯烷酮、聚丙烯酸酯、蜡、聚乙烯聚氧丙烯嵌段聚合物、羊毛脂、糖(如乳糖、葡萄糖、蔗糖)、淀粉(如玉米淀粉、马铃薯淀粉)、纤维素及其衍生物(如羧甲基纤维素钠、乙基纤维素、醋酸纤维素)、黄芪胶粉、麦芽、明胶、滑石粉、赋形剂(如可可脂和栓剂蜡)、油类(如花生油、棉籽油、红花油、芝麻油、橄榄油、玉米油、大豆油)、二醇类(如丙二醇或聚乙二醇)、酯类(如油酸乙酯和月桂酸乙酯)、琼脂、无毒相容的润滑剂(如十二烷基硫酸钠和硬脂酸镁)、着色剂、释放剂、包衣剂、乳化剂、甜味剂、调味剂、香料、防腐剂、抗氧化剂等也可根据配方师的判断存在于组合物中。
尽管组合物中组分的量可以根据制备的组合物的类型而变化,但一般而言,全身性组合物可以包括0.01%至50%的化合物(例如PLE或磷脂-flavagline缀合物)和50%到99.99%的一个或多个载体。用于肠胃外给药的组合物通常可以包含0.1%至10%的化合物和90%至99.9%的一种或多种载体。口服剂型可以包括例如至少约5%,或约25%至约50%的化合物。口服剂量组合物可包含约50%至约95%的载体,或约50%至约75%的载体。与所公开的化合物结合使用的载体的量足以提供实用量的组合物用于每单位剂量的化合物给药。制备可用于本发明方法的剂型的技术和组合物描述于以下参考文献:ModernPharmaceutics,第9章和第10章,Banker&Rhodes,eds.(1979);Lieberman等人,Pharmaceutical Dosage Forms:Tablets(1981);和Ansel,Introduction toPharmaceutical Dosage Forms,第二版,(1976)。
在一些实施方案中,药物组合物基本上由治疗有效量的本文公开的化合物或其药学可接受的盐组成。
液体剂型包括但不限于药学上可接受的乳剂、微乳剂、溶液、混悬剂、糖浆剂和酏剂。固体剂型包括但不限于胶囊、片剂、丸剂、粉剂、水门汀、油灰和颗粒剂。本发明化合物的局部或透皮给药的剂型包括但不限于软膏剂、糊剂、乳膏剂、洗剂、凝胶剂、粉末剂、溶液剂、喷雾剂、吸入剂或贴剂。
液体载体或媒介物可以是溶剂或液体分散介质,包括例如水、乙醇、多元醇(例如甘油、丙二醇、液体聚乙二醇等)、植物油、无毒甘油酯及其合适的混合物。
药物组合物可以是适合注射或输注的剂型,例如无菌水溶液或分散体或包含活性成分的无菌粉末,其适用于临时制备无菌可注射或可输注溶液或分散体。最终剂型在生产和储存条件下应该是无菌的、流动的和稳定的。可以通过至少将本文所公开的化合物或其药学可接受的盐以所需量的适当溶剂与所需的各种其他所需成分掺入适当的溶剂中,可选地随后过滤灭菌来制备无菌可注射溶液。在用于制备无菌可注射溶液的无菌粉末的情况下,制备方法可以包括真空干燥和冷冻干燥技术,其产生一种或多种活性成分粉末加上无菌溶液中存在的任何其他所需成分。
在一些实施方案中,组合物是溶液,例如适合通过输注或注射给药的溶液。溶液可以在水中制备,可选与无毒表面活性剂混合。也可以在甘油、液体聚乙二醇、三醋酸甘油酯及其混合物和油中制备分散体。这些制剂可能含有防腐剂以防止微生物生长。可以通过各种抗菌剂和抗真菌剂来防止微生物的作用,例如对羟基苯甲酸酯、氯丁醇、苯酚、山梨酸、硫柳汞(thimerosal)等。
可通过在可生物降解的聚合物如聚丙交酯-聚乙交酯(polylactide-polyglycolide)中形成本文所公开的化合物或其药学上可接受的盐的微囊基质来制备可注射形式。根据化合物与聚合物的比例和所用特定聚合物的性质,可以控制药物释放速率。其他可生物降解的聚合物的例子包括聚(原酸酯)和聚(酸酐)。也可通过将药物包埋在与身体组织相容的脂质体或微乳液中来制备可注射制剂。
在一些实施方案中,组合物可以包含至少一种如本文所述的化合物和至少一种另外的抗癌药。可用于本公开的抗癌药物包括但不限于紫杉醇、伊立替康、托泊替康、吉西他滨、顺铂、格尔德霉素、mertansine、阿比特龙、阿法替尼、aminolevulinic acid、阿瑞匹坦、阿西替尼、阿扎胞苷、belinostat、苯达莫司汀、bexarotene、博来霉素、硼替佐米、bosutinib、白消安、cabazitazel、卡博替尼、卡培他滨、卡铂、carfilzomib、卡莫司汀、ceritinib、cetuximab、苯丁酸氮芥、clofarabine、crizotinib、cyclophosphamide、阿糖胞苷、dabrafenib、达卡巴嗪、dactinomycin、dasatinib、daunorubicin、decitabine、denosumab、右雷佐生、多西他赛、dolastatins(例如monomethyl auristatin E)、doxorubicin、enzalutamide、epirubicin、eribulin mesylate、厄洛替尼、依托泊苷、依维莫司、氟尿苷、磷酸氟达拉滨、氟尿嘧啶、ganetespib、吉非替尼、吉妥珠单抗奥佐米星、六甲基三聚氰胺、羟基脲、替伊莫单抗、ibrutinib、idelalisib、异环磷酰胺、伊马替尼、易普利姆玛、伊沙匹隆、拉帕替尼、亚叶酸钙、洛莫司汀、美登木素生物碱、二氯甲基二乙胺、美法仑、巯嘌呤、美司钠、甲氨蝶呤、丝裂霉素C、米托坦、米托蒽醌、奈拉滨、奈非那韦、尼罗替尼、obinutuzumab、奥法木单抗、omacetaxine mepesuccinate、奥沙利铂、帕尼单抗、帕唑帕尼、培门冬酶、派姆单抗、培美曲塞、pentosatatin、帕妥珠单抗、plicamycin、泊马度胺、帕纳替尼盐酸盐、普拉曲沙、甲基苄肼、二氯化镭223、雷莫芦单抗、瑞格拉菲尼、retaspimycin、鲁索替尼、甲基环己亚硝脲、司妥昔单抗、索拉非尼、链脲菌素、sunitinib malate、tanespimycin、替莫唑胺、莫司、替尼泊苷、沙利度胺、硫鸟嘌呤、噻替派、托瑞米芬、曲美替尼、曲妥单抗、凡德他尼、维莫非尼、长春花碱、长春新碱、长春瑞滨、vismodegib、伏立诺他和阿柏西普。当前已知或能够充当抗癌药物的任何化合物也可用于本公开。
5.给药
本文所述的化合物或其药学上可接受的盐或本文所述的药物组合物可以施用于受试者。考虑到诸如特定受试者的年龄、性别、体重和状况以及给药途径等因素,化合物和组合物可以以医学领域技术人员已知的剂量和技术给药。
本发明的化合物和组合物可以预防性或治疗性给药。在预防性给药中,化合物和组合物可以以诱导预防性反应的有效量给药。在治疗应用中,可以将有效量的化合物和组合物施用于有需要的受试者以引发治疗效果。
例如,化合物的治疗有效量可以是约1mg/kg至约1000mg/kg、约5mg/kg至约950mg/kg、约10mg/kg至约900mg/kg、约15mg/kg至约850mg/kg、约20mg/kg至约800mg/kg、约25mg/kg至约750mg/kg、约30mg/kg至约700mg/kg、约35mg/kg至约650mg/kg、约40mg/kg至约600mg/kg、约45mg/kg至约550mg/kg、约50mg/kg至约500mg/kg、约55mg/kg至约450mg/kg、约60mg/kg至约400mg/kg、约65mg/kg至约350mg/kg、约70mg/kg至约300mg/kg、约75mg/kg至约250mg/kg、约80mg/kg至约200mg/kg、约85mg/kg至约150mg/kg和约90mg/kg至约100mg/kg。
化合物可以通过本领域熟知的方法施用,如记载于Donnelly等人(Ann.Rev.Immunol.1997,15,617-648);Felgner等人(美国专利No.5,580,859,颁发于Dec.3,1996);Felgner(美国专利No.5,703,055,颁发于Dec.30,1997);以及Carson等人(美国专利No.5,679,647,颁发于Oct.21,1997),所有这些专利的全部内容通过引用并入本文。该化合物可以复合成颗粒或珠子,可以例如使用疫苗枪施用于个体。本领域技术人员知道,药学上可接受的载体的选择包括生理学上可接受的化合物,取决于例如给药途径。
化合物可以通过多种途径递送。典型的递送途径包括肠胃外给药,例如皮内、肌内或皮下递送。其他途径包括口服、鼻内、阴道内、透皮、静脉内、动脉内、肿瘤内、腹膜内和表皮途径。在一些实施方案中,化合物通过静脉内、动脉内或腹膜内施用于受试者。在一些实施方案中,将化合物由静脉内施用于受试者。在一些实施方案中,将化合物口服给予受试者。
在一些实施方案中,化合物以控释制剂给药。例如,该化合物可以释放到循环中。在一些实施方案中,化合物可以在至少约1天、至少约2天、至少约3天、至少约4天、至少约5天、至少约6天、至少约7天、至少约1周、至少约1.5周、至少约2周、至少约2.5周、至少约3.5周、至少约4周或至少约1个月的时间段内释放。
化合物可以单剂量或间歇或重复剂量给药。例如,化合物可以每小时、2小时、4小时、8小时、12小时、25小时、36小时、2天、3天、4天、5天、6天、1周、2周、3周或4周施用一次。
6.方法
本文所述化合物的选择性肿瘤靶向的基础在于癌细胞的质膜与大多数正常细胞的质膜之间的差异。磷脂醚(PLE)分子利用肿瘤细胞经历的代谢转变来产生快速细胞分裂所需的能量。肿瘤增强了利用β氧化途径将长链脂肪酸(LCFA)转化为能量的能力。为了增加LCFA的摄取,肿瘤细胞会改变细胞膜,形成被称为“脂筏”的特殊微区。由于代谢变化和对磷脂的需求,会形成脂筏。在肿瘤细胞内,这些区域已经变得过多并稳定,使它们成为潜在的肿瘤特异性靶标。具体来说,癌细胞膜在脂筏中高度富集。在正常组织中,脂筏的存在是有限且短暂的(约2纳秒)。在肿瘤中,脂筏的存在增加并稳定(长达10天)。癌细胞的脂筏比健康细胞多五到十倍。此外,已证明脂筏在几乎所有肿瘤类型和100%测试的单个癌细胞中都非常丰富。脂筏是膜磷脂双层的高度组织化和特化区域,含有高浓度的各种信号分子、鞘脂、鞘糖脂和胆固醇,并用于组织细胞表面和细胞内信号分子(例如,生长因子和细胞因子受体、磷脂酰肌醇3-激酶(PI3K)/Akt生存途径)。数据表明,脂筏作为磷脂醚的入口。这些化合物相对于非癌细胞对癌细胞的显著选择性归因于PLE对胆固醇的高亲和力和癌细胞中富含胆固醇的脂筏。脂筏结构的破坏抑制了PLE被癌细胞吸收,这一事实突显了脂筏所起的关键作用。已经表明,当脂筏被阻止形成时,PLE的摄取减少了60%。这些特征与提供磷脂药物缀合物快速内化的脂筏相结合,使它们成为理想的靶标。
本文公开的化合物,例如PLE类似物,可以是LCFA模拟物。本文公开的分子已经进行了与靶向肿瘤细胞上的脂筏相关的广泛的结构活性关系(SAR)分析,并已显示出与这些区域特异性结合。本文公开的分子提供进入细胞质并沿细胞质内的高尔基体网络转运至内质网和线粒体的直接入口。在一些实施方案中,本文公开的化合物包括独特设计的与flavagline(FLV)类似物缀合的磷脂醚。FLV是有效的细胞毒素,可抑制翻译、细胞周期进程并诱导细胞凋亡。
如本文所述的化合物或其药学可接受的盐或包含本文所述的化合物的组合物可用于治疗癌症。在一个方面,提供了一种治疗有需要的受试者的癌症的方法,包括向受试者施用有效量的如本文所述的化合物、或其药学可接受的盐、或包含本文所述化合物的组合物。
另一方面,本公开提供了如本文所述的化合物或其药学上可接受的盐,用于治疗有需要的受试者的癌症的用途。
在另一方面,本公开提供了如本文所述的化合物或其药学上可接受的盐在制备用于治疗有需要的受试者的癌症的药物中的用途。
在一个方面,本公开提供了一种将药物靶向受试者中的肿瘤或癌症细胞的方法,该方法包括向受试者施用如本文所述的化合物,或其药学可接受的盐,或包含本文所述的化合物的组合物。靶向可导致本发明化合物靶向递送至癌细胞和/或靶向治疗癌症。
在一些实施方案中,化合物或其药学上可接受的盐定位或行进至肿瘤或癌细胞的细胞质或细胞器。
在一些实施方案中,所述化合物或其药学上可接受的盐对受试者中的癌细胞具有选择性。
在一些实施方案中,将化合物或其药学上可接受的盐掺入到比健康细胞多至少约2倍的肿瘤或癌细胞中。化合物或其药学上可接受的盐可以掺入比健康细胞多至少约2倍、至少约3倍、至少约4倍、至少约5倍、至少约6倍,至少约7倍、至少约8倍、至少约9倍、至少约10倍、至少约15倍、至少约20倍、至少约25倍、至少约30倍的肿瘤或癌细胞中。
用本文所述的化合物、或其药学可接受的盐、或包含如本文所述的化合物的组合物治疗的癌症包括,但不限于:乳腺癌,男性乳腺癌消化道/胃肠道癌,包括肛门癌、阑尾癌、肝外胆管癌、胃肠道类癌肿瘤、结肠癌、食道癌、胆囊癌、胃癌、胃肠道间质瘤(“gist”)、胰岛细胞瘤、成人原发性肝癌、儿童肝癌、胰腺癌、直肠癌、小肠癌和胃癌;内分泌和神经内分泌癌,包括胰腺腺癌、肾上腺皮质癌、胰腺神经内分泌肿瘤、默克尔细胞癌、非小细胞肺神经内分泌肿瘤、小细胞肺神经内分泌肿瘤、甲状旁腺癌、嗜铬细胞瘤、垂体瘤和甲状腺癌;眼癌,包括眼内黑色素瘤和视网膜母细胞瘤;泌尿生殖系统癌,包括膀胱癌、肾(肾细胞)癌、阴茎癌、前列腺癌、移行细胞肾盂和输尿管癌、睾丸癌、尿道癌和肾母细胞瘤;生殖细胞癌,包括儿童中枢神经系统癌、儿童颅外生殖细胞肿瘤、性腺外生殖细胞肿瘤、卵巢生殖细胞肿瘤和睾丸癌;妇科癌症包括宫颈癌、子宫内膜癌、妊娠滋养细胞肿瘤、卵巢上皮癌、卵巢生殖细胞瘤、子宫肉瘤、阴道癌和外阴癌;头颈癌,包括下咽癌、喉癌、唇癌和口腔癌、隐匿性原发性转移性鳞状颈癌、口腔癌、鼻咽癌、口咽癌、鼻窦和鼻腔癌、甲状旁腺癌、咽癌、唾液腺癌和喉癌;白血病,包括成人急性淋巴细胞白血病、儿童急性淋巴细胞白血病、成人急性髓细胞白血病、儿童急性髓细胞白血病、慢性淋巴细胞白血病、慢性髓细胞白血病和毛细胞白血病;淋巴瘤,包括艾滋病相关淋巴瘤、皮肤t细胞淋巴瘤、成人霍奇金淋巴瘤、儿童霍奇金淋巴瘤、妊娠期霍奇金淋巴瘤、阿利贝尔氏病(mycosis fungoides)、成人非霍奇金淋巴瘤、儿童非霍奇金淋巴瘤、妊娠期非霍奇金淋巴瘤、原发性中枢神经系统淋巴瘤、Sézary综合征和巨球蛋白血症;肌肉骨骼癌,包括尤文肉瘤、骨肉瘤和恶性骨纤维组织细胞瘤、儿童横纹肌肉瘤和软组织肉瘤;神经系统癌症,包括成人脑瘤、儿童脑瘤、星形细胞瘤、脑干神经胶质瘤、中枢神经系统非典型畸形/横纹肌样瘤、中枢神经系统胚胎肿瘤、颅咽管瘤、室管膜瘤、神经母细胞瘤、原发性中枢神经系统(CNS)淋巴瘤;呼吸道/胸部癌症,包括非小细胞肺癌、小细胞肺癌、恶性间皮瘤、胸腺瘤和胸腺癌;和皮肤癌,包括卡波西肉瘤、黑色素瘤和鳞状细胞癌。在特定实施方案中,癌症可以是黑色素瘤、肺癌、结直肠癌、乳腺癌或其组合。
在一些实施方案中,所述癌症是黑色素瘤、脑癌、肺癌、肾上腺癌、肝癌、肾癌或肾癌、胰腺癌、食道癌、胃癌、胃癌、结肠癌、结直肠癌、肛门癌、前列腺癌、卵巢癌、乳腺癌、宫颈癌、淋巴瘤、白血病、骨髓瘤、血癌、肝癌、视网膜母细胞瘤、神经胶质瘤、肉瘤、母细胞瘤、鳞状细胞癌、腺癌或其组合。在一些实施方案中,所述癌症是黑色素瘤、肺癌、结直肠癌、乳腺癌或其组合。
在一些实施方案中,所述癌症可包含一种或多种循环肿瘤细胞。例如,一种或多种循环肿瘤细胞可以选自乳腺癌、肺癌、甲状腺癌、宫颈癌、黑色素瘤、鳞状细胞癌、前列腺癌、胰腺癌、结直肠癌、癌症干细胞和恶性浆细胞。
在一些实施方案中,所述癌症可以是转移性的。例如,转移性癌症可以选自由乳腺癌、肺癌、黑色素瘤和结直肠癌组成的组。
在一些实施方案中,所述癌症可以包括癌症干细胞。例如,癌症干细胞可以选自乳腺癌、肺癌、黑色素瘤和结直肠癌。
在一些实施方案中,所述肺癌可包括小细胞肺癌、非小细胞肺癌或其组合。
在一些实施方案中,所述黑色素瘤可包括浅表扩散性黑色素瘤、结节性黑色素瘤、恶性雀斑样痣黑色素瘤、肢端雀斑样黑色素瘤、无黑色素性黑色素瘤、母黑色素瘤、spitzoid黑色素瘤、促结缔组织增生性黑色素瘤或其组合。
在一些实施方案中,所述结直肠癌包括腺癌。
在一些实施方案中,所述乳腺癌可包括浸润性乳腺导管癌、转移性乳腺癌、炎性乳腺癌、三阴性乳腺癌、导管原位癌或其组合。在一些实施方案中,癌症是乳腺癌,受试者可以是雌激素受体阳性、雌激素受体阴性和孕激素受体阴性、表达HER2(HER2+)、不表达HER2(HER2-)或其组合。
在一些实施方案中,受试者是人,例如成人和婴儿。在一些实施方案中,受试者是动物,例如哺乳动物。
所述方法可以包括以本文所述的量施用本发明化合物或其药学上可接受的盐。在一些实施方案中,所述的方法包括施用约0.0001至约1000mg/kg的如本文所述的化合物,或施用其药学可接受的盐。可以通过在其动物模型中比较它们的体外活性和体内活性来确定化合物的可用剂量。用于将啮齿动物、猪和其他动物的有效剂量外推到人类的方法是本领域已知的;例如,参见美国专利No.4,938,949。
在一些实施方案中,本文公开的化合物或其药学上可接受的盐或药物组合物可以通过口服给药或静脉内给药来给药。然而,一般而言,合适的剂量通常在约0.0001mg/kg至约1000mg/kg的范围内,例如约0.001mg/kg至约10.0mg/kg。例如,合适的剂量可以在每天约0.001mg/kg至约5.0mg/kg体重的范围内,例如每天约0.01mg/kg至约1.0mg/kg接受者体重,每天约0.01mg/kg至约3.0mg/kg接受者体重,每天约0.1mg/kg至约5.0mg/kg接受者体重,每天约0.2mg/kg至4.0mg/kg接受者的体重。该化合物可以以单位剂型给药;例如,每单位剂型含有1至100mg、10至100mg或5至50mg的活性成分。
所需剂量可以方便地以单剂量或以适当间隔施用的分剂量存在,例如,作为每天两个、三个、四个或更多个亚剂量。亚剂量本身可以进一步划分,例如,分成多个离散的、间隔松散的给药。
合适的体内给药剂量和具体的给药方式可以根据年龄、体重、疾病的严重程度和所治疗的哺乳动物物种、所用的具体化合物和这些化合物的具体用途而变化。可通过已知方法来确定达到所需结果的有效剂量水平,例如人体临床试验、体内研究和体外研究。例如,本文公开的化合物或其药学上可接受的盐的有效剂量可以通过比较它们的体外活性和动物模型中的体内活性来确定。这种比较可以通过与已建立的药物进行比较来完成。
可以单独调整剂量和间隔以提供足以维持调节作用或最小有效浓度(MEC)的活性部分的血浆水平。每种化合物的MEC会有所不同,但可以根据体内和/或体外数据进行估计。达到MEC所需的剂量将取决于个体特征和给药途径。然而,FIPLC测定或生物测定可用于确定血浆浓度。剂量间隔也可以使用MEC值来确定。组合物应使用维持血浆水平高于MEC达10-90%,优选30-90%,最优选50-90%的方案给药。在局部给药或选择性摄取的情况下,药物的有效局部浓度可能与血浆浓度无关。
本文所述的组合物可以与另外的组合物一起施用以延长组合物的稳定性、递送和/或活性,或者与另外的治疗剂组合,或者在施用另外的治疗剂之前或之后提供。联合治疗包括施用含有一种或多种本文所述化合物和一种或多种另外的药剂的单一药物剂型,以及施用化合物和每种另外的药剂,以其自己的单独的药物剂型。例如,本文所述的化合物可以与本文所述的另外的抗癌药一起施用于受试者。
7.实施例
实施例1
化学合成
PLE。PLE是根据下面的方案1合成的:
方案1
Flavagline类化合物。Flavagline可市购。FLV1和FLV3购自Haoyuan ChemexpressCo.(中国上海)。FLV1和FLV3根据以下方案2交替合成:
方案2
PLE-flavagline构建体。CLR 1852(化合物(9))和CLR 1865(化合物(8))根据以下方案3合成:
方案3
CLR 1899的合成。根据方案4合成CLR 1899。通过NMR和MS数据验证结构。
方案4
实施例2
肿瘤细胞中脂筏的存在
用霍乱毒素亚基B(cholera toxin subunit B)染色超过100个细胞系,用4%甲醛固定,并用filipin III染色30分钟。如图1A-图1D所示,几乎所有测试的肿瘤类型都显示出细胞膜中的高脂筏浓度(超过100个细胞系、新鲜的患者样本等)。如图1E所示,A549细胞与正常成纤维细胞共培养48小时,然后用霍乱毒素亚基B染色,用4%甲醛固定,并用filipinIII染色30分钟。这些结果表明,肿瘤细胞比正常细胞具有更高浓度的脂筏。
实施例3
PDC选择摄入肿瘤细胞
将正常成纤维细胞和Caki-2肿瘤细胞(人透明细胞肾细胞癌)铺板并共培养过夜(图1F)。然后将细胞与5μM CLR1501(化合物(1))在37℃的完全培养基中孵育24小时。第二天洗涤细胞并用细胞核染色剂(Hoescht 33342)共同染色。CLR 1501被激发,然后用Alexa-Fluor 488过滤器检测。CLR 1501在Caki-2细胞中高度定位,在正常成纤维细胞中最少。
实施例4
破坏脂筏降低PDC摄入
将A549细胞过夜铺板到单独的孔中。第二天,细胞要么不处理(图1G),要么用甲基β-环糊精(图1H)处理,甲基β-环糊精已显示选择性破坏脂筏。然后将所有细胞与5μM CLR1501(化合物(1))一起孵育24小时。与未处理的细胞(图1G)相比,破坏A549细胞中的大多数脂筏导致CLR 1501(图1H)的摄取减少60%。
实施例5
PDC追踪到内质网
将人前列腺腺癌细胞(PC3)铺板在微孔板VI(Ibidi,Verona,WI)上过夜,然后在完全培养基中与5μM CLR1501(化合物(1))在37℃下培养24小时。洗涤后,每个方案使用对细胞进行共染色,并使用Nikon A1R共聚焦光学显微镜进行成像。CLR1501和ER被激发并使用Alexa-Fluor 488使用标准荧光素过滤器进行检测。CLR 1501在恶性肿瘤中与ER共定位(图1I-图1K),但不与正常细胞共定位(未显示)。
实施例6
PDC追踪到内质网
PC3(IV级,人前列腺腺癌细胞)细胞系在微载玻片VI(Ibidi,Verona,WI)上培养过夜。第二天,将细胞与5μM CLR1501(化合物(1))在37℃完全培养基中培养24小时。第二天用PBS洗涤后,用细胞核染料(Hoechst 33342)和线粒体标记物(Invitrogen,Carlsbad,CA)对细胞进行共染色。使用Nikon A1R共聚焦显微镜观察细胞。CLR 1501使用Alexa-Fluor 488过滤器进行激发和检测,而细胞核染色和线粒体染色分别使用DAPI过滤器和Texas-Red过滤器进行激发和检测。将CLR 1501与线粒体共定位(图1L-图1N)。
实施例7
PDC提供体内靶向递送
用1mg CLR 1502(化合物(2))注射忍受结直肠(HCT-116)肿瘤的裸鼠并在Pearl红外成像系统上成像。不同的颜色反映了CLR 1502随时间变化的强度。注射后约5.5小时,肿瘤仍呈红色(反映CLR 1502的最高分布)(图2)。在24小时内,获得了CLR 1502的最大分布。在30分钟内记录了初始目标(未显示)。
实施例8
细胞毒性PDC提供靶向和潜在改善的治疗指数
将A549(人肺腺癌)细胞和正常人真皮成纤维细胞(NHDF)铺板在96孔培养皿中过夜。所有细胞都单独用增加浓度的母体细胞毒性化合物(FLV1或FLV3)或PDC(通过可断裂连接子与PLE部分缀合的母体细胞毒性化合物,CLR 1865(化合物(8))或CLR 1852(化合物(9)))处理。母体细胞毒性化合物显示对A549细胞的效力与对NHDF细胞的效力几乎相同。然而,PDC分子显示出对A549细胞的选择性(图3)。PDC分子显示对NHDF细胞几乎没有影响,直到最高浓度和接近A549细胞中母体分子的效力。PDC分子对肿瘤细胞和正常细胞的细胞毒性之间的差异可能表明有可能提高母体分子的治疗指数。
实施例9
细胞毒性PDC提供靶向
评估了CLR 1852(化合物(9))在A375(人黑色素瘤)和HEK293(人胚肾)细胞中的摄取。将细胞与CLR 1852(化合物(9))一起培养24小时。显示在治疗24小时内,与正常细胞相比,肿瘤细胞的PDC增加了6至28倍(图4)。
实施例2-9的结果表明磷脂醚分子通过脂筏靶向肿瘤细胞。与正常细胞相比,即使在共培养中,PDC也显示出明显摄取入肿瘤细胞。进入肿瘤细胞后,PDCs追踪到线粒体和内质网。在体内,PDCs在肿瘤内靶向并迅速积累。细胞毒性PDC提供了改进的靶向性和提高安全性的潜力。
实施例10
PLE的细胞摄取
各种癌细胞系在体外和体内暴露于荧光标记的PLE(CLR 1501,化合物(1))。连续24小时测量肿瘤细胞摄取。结果示于表1和图5、图6和图7。PLE化合物对肿瘤和癌细胞具有特异性。
将荧光标记的PLE(CLR 1501,化合物(1))施用于良性组织,没有观察到摄取(表2)。
表1.PLE的体外细胞摄取
表2.CLR1404在良性组织中的摄取
实施例11
PLE-Flavagline缀合物在癌细胞中的活性
将PLE-flavagline缀合物CLR 1852(化合物(9))和CLR 1865(化合物(8))施用于细胞系A375(人恶性黑色素瘤)、A549(人肺腺癌)、HCT 116(人结肠癌)和NHDF(正常人真皮成纤维细胞)。计算IC50。结果如表3所示。
表3.多种癌症细胞系中的IC50(μM/mL)
CLR 1852的细胞毒性在不同浓度下测定。如图8所示,与单独的FLV3相比,CLR1852显示出适度的效力损失,这可能是由于释放不完全所致。
检验了CLR1865(化合物(8))、CLR 1852(化合物(9))和FLV3在血浆中的稳定性,丙胺太林(propantheline)作为对照(表4)。少量分子暴露于血浆,然后通过HPLC或MS分析血浆以确定分子是否被降解。CLR 1865和CLR1852表现出优异的人血浆稳定性。CLR 1852在小鼠血浆中的表现优于CLR 1865。CLR 1865仅在小鼠血浆中稳定3.3小时。CLR 1852在血浆中稳定至少7小时。
表4.血浆稳定性
在小鼠中检验了CLR 1865和CLR 1852的治疗指数(TI)(表5)。表5列出了给予小鼠的剂量,以及治疗后存活的小鼠数量(“3/3”表示3只小鼠中有3只存活)。与单独的FLV3相比,CLR 1852和CLR 1865在耐受性方面均表现出出色的改善。CLR 1852没有达到最大耐受剂量(MTD),可能是因为它的溶解度限制了更大的剂量。CLR 1865的MTD介于5和10mg/kg之间。CLR 1852的体内治疗指数至少为25,CLR 1865的体内治疗指数至少为12.5。
表5.体内治疗指数
剂量(mg/kg) | FLV3 | CLR 1852 | CLR 1865 |
0.1 | 3/3 | 3/3 | 3/3 |
0.25 | 3/3 | 3/3 | 3/3 |
0.5 | LD | 3/3 | 3/3 |
1.0 | n/a | 3/3 | 3/3 |
5.0 | n/a | 3/3 | 3/3 |
10.0 | n/a | 3/3 | 2/3 |
检查了CLR 1852在HCT 116细胞(人结肠癌)中的功效。CLR 1852以每个1mg/mg的三个剂量给药于HCT 116细胞。与载体相比,CLR 1852从大约27天开始减少肿瘤体积(图9)。与载体相比,CLR 1582引起适度的体重减轻,可能是由于毒性(图10)。与单独的FLV3相比,CLR 1582提供的耐受性至少提高了六倍(数据未显示)。
将CLR 1852和FLV3单独施用于A375和A549细胞。使用LC/MS测量细胞裂解物和生长培养基中的FLV3水平。如图11所示,24小时后细胞裂解物中存在高水平的FLV3。24小时后,中等水平的FLV3存在于生长培养基中。细胞内FLV3的水平在24小时似乎趋于平稳,而FLV3的细胞外水平继续增加。
实施例12
CLR 1899在癌细胞中的活性
将CLR 1899施用于细胞系A375(人恶性黑色素瘤)、A549(人肺腺癌)、HCT 116(人结肠癌)和NHDF(正常人真皮成纤维细胞)。体外细胞毒性结果见表6。
表6
为了确定CLR 1899在体内是否耐受,将化合物以0.5mg/kg、1.0mg/kg或2.0mg/kg的剂量水平静脉内给予健康C57BL/6小鼠,并观察体重变化(图12)。CLR 1899在重复给药期间未显示通过体重变化测量的毒性或不良事件。在MCF-7异种移植模型中研究了CLR 1899的体内功效(图13,每个剂量组10只小鼠)。记录肿瘤体积的减少。在这些研究中,CLR 1899在阻止或减缓肿瘤生长方面表现出与多西紫杉醇相当的活性。
具体方面的上述描述将如此充分地揭示本发明的一般性质,以致其他人可以通过应用本领域技术内的知识,容易地修改和/或适应这些具体方面的各种应用,而无需过度实验,而不背离本公开的一般概念。因此,基于本文所呈现的教导和指导,此类改变和修饰旨在落入所公开方面的等同物的含义和范围内。应当理解,本文中的措辞或术语是出于描述而非限制的目的,使得本说明书的术语或措辞将由本领域技术人员根据教导和指导来解释。
本公开的广度和范围不应受任何上述示例性方面的限制,而应仅根据所附权利要求及其等同物来定义。
本申请中引用的所有出版物、专利、专利申请和/或其他文件通过引用整体并入,其出于的所有目的的程度与每个单独的出版物、专利、专利申请和/或其他文件单独指出通过引用并入出于的所有目的相同。
为了完整起见,本公开的各个方面在以下编号的条款中列出:
条款1.式(I)化合物,或其药学可接受的盐,
其中Z是flavagline类似物。
条款2.条款1所述的化合物,选自由下列组成的组:
或其药学可接受的盐。
条款3.一种包含条款1-2中任一所述的化合物或其药学可接受的盐,和药学可接受载体的药物组合物。
条款4.一种治疗受试者癌症的方法,包含向受试者给予有效量的条款1-2中任一所述的化合物或其药学可接受的盐。
条款5.一种靶向药物至受试者肿瘤或癌细胞的方法,所述的方法包含给予受试者条款1-2中任一所述的化合物或其药学可接受的盐。
条款6.条款4-5中任一所述的方法,其中所述化合物或其药学可接受的盐,定位于或途径肿瘤或癌细胞的细胞质或细胞器。
条款7.条款4-6中任一所述的方法,其中所述化合物或其药学可接受的盐,对受试者中癌细胞有选择性。
条款8.条款4-7中任一所述的方法,其中化合物或其药学可接受的盐,掺入比健康细胞多至少约2倍或更多的肿瘤或癌细胞。
条款9.条款4-8中任一所述的方法,其中癌症是黑色素瘤、脑癌、肺癌、肾上腺癌、肝癌、肾癌或肾癌、胰腺癌、食道癌、胃癌、胃癌、结肠癌、结直肠癌、肛门癌、前列腺癌、卵巢癌、乳腺癌、宫颈癌、淋巴瘤、白血病、骨髓瘤、血癌、肝癌、视网膜母细胞瘤、神经胶质瘤、肉瘤、胚细胞瘤、鳞状细胞癌、腺癌或其组合。
条款10.条款4-9中任一所述的方法,其中癌症是黑色素瘤、肺癌、结直肠癌、乳腺癌或其组合。
条款11.条款4-10中任一所述的方法,其中
所述肺癌包括小细胞肺癌、非小细胞肺癌或其组合;
所述黑色素瘤包括浅表扩散性黑色素瘤、结节性黑色素瘤、恶性雀斑样痣黑色素瘤、肢端雀斑样黑色素瘤、无黑色素性黑色素瘤、母黑色素瘤、spitzoid黑色素瘤、促结缔组织增生性黑色素瘤或其组合;
所述结直肠癌包括腺癌;或者
所述乳腺癌包括浸润性乳腺导管癌、转移性乳腺癌、炎性乳腺癌、三阴性乳腺癌、导管原位癌或其组合。
条款12.条款4-11中任一所述的方法,其中癌症包含癌症干细胞。
条款13.条款4-12中任一所述的方法,其中癌症包含转移性癌细胞。
条款14.条款4-13中任一所述的方法,其中癌症包含循环肿瘤细胞。
条款15.条款4-14任一所述的方法,其中受试者是人类。
Claims (15)
3.一种包含权利要求1-2中任一项所述的化合物或其药学可接受的盐和药学可接受的载体的药物组合物。
4.一种治疗有需要的受试者癌症的方法,所述方法包含向受试者给予有效量的权利要求1-2中任一项所述的化合物或其药学可接受的盐。
5.一种将药物靶向受试者肿瘤或癌细胞的方法,所述方法包含向受试者给予权利要求1-2中任一项所述的化合物或其药学可接受的盐。
6.根据权利要求4-5中任一项所述的方法,其中所述化合物或其药学可接受的盐,定位于或途径肿瘤或癌细胞的细胞质或细胞器。
7.根据权利要求4-6中任一项所述的方法,其中所述化合物或其药学可接受的盐,对受试者中的癌症细胞有选择性。
8.根据权利要求4-7中任一项所述的方法,其中所述化合物或其药学可接受的盐,掺入比健康细胞多至少大约两倍的肿瘤和癌细胞中。
9.根据权利要求4-8中任一项所述的方法,其中所述癌症是黑色素瘤、脑癌、肺癌、肾上腺癌、肝癌、肾癌或肾癌、胰腺癌、食道癌、胃癌、胃癌、结肠癌、结直肠癌、肛门癌、前列腺癌、卵巢癌、乳腺癌、宫颈癌、淋巴瘤、白血病、骨髓瘤、血癌、肝癌、视网膜母细胞瘤、神经胶质瘤、肉瘤、胚细胞瘤、鳞状细胞癌、腺癌或其组合。
10.根据权利要求4-9中任一项所述的方法,其中所述癌症是黑色素瘤、肺癌、结直肠癌、乳腺癌或其组合。
11.根据权利要求4-10中任一项所述的方法,其中
所述肺癌包括小细胞肺癌、非小细胞肺癌或其组合;
所述黑色素瘤包括浅表扩散性黑色素瘤、结节性黑色素瘤、恶性雀斑样痣黑色素瘤、肢端雀斑样黑色素瘤、无黑色素性黑色素瘤、母黑色素瘤、spitzoid黑色素瘤、促结缔组织增生性黑色素瘤或其组合;
所述结直肠癌包括腺癌;或者
所述乳腺癌包括浸润性乳腺导管癌、转移性乳腺癌、炎性乳腺癌、三阴性乳腺癌、导管原位癌或其组合。
12.根据权利要求4-11中任一项所述的方法,其中所述癌症包含癌症干细胞。
13.根据权利要求4-12中任一项所述的方法,其中所述癌症包含转移性癌细胞。
14.根据权利要求4-13中任一项所述的方法,其中所述癌症包含循环肿瘤细胞。
15.根据权利要求4-14中任一项所述的方法,其中所述受试者是人类。
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